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United States Patent 3,125,570 3,16-DIAMINO-3,5-PREGNADIENES AND PROCESSFOR PREPARING SAME Laszl Vargha, Marta Ratios, Endre Kasztreiner, and

Laszl Szporny, all of Budapest, Hungary, assignors to Richter GedeonVegyszeti Gyar RT., Budapest, Hungary No Drawing. Filed Aug. 21, 1962,Ser. No. 218,464 6 Claims. (Cl. 260-2395) This invention relates to newand useful basic derivatives of steroid compounds. More particularly itis concerned with novel derivatives of certain 3-enamino-A steroidssubstituted by a hydroxyl group in the 17 aand by a basic substituent inthe 16-position.

It is known that various steroid compounds, e.g. Adehydro-l7a-methyltestosterone and nor-androstenolone phenylpropionateshow therapeutically useful anabolic effects; it is however, animportant disadvantage of these known anabolic steroids that they exertsimultaneously also undesirable hormonal (e.g. androgenic or estrogenic)side effects which impose important restrictions on their applicability.

It has surprisingly been found that the new 3-enamiuo- A -steroids ofthe general Formula I OH 1 NRR' TURN-Q with a secondary amine of thegeneral Formula HI HNRR' III (X and NRR have in these formulae the samemeaning as above). Two basic groups are being introduced thereby intothe molecule, one of these into the 3-position, while an enaminestructure is formed; the other basic group is introduced into' the16-position, under simultaneous splitting of the 16,17-epoxide ring,whereby an a-hydroxyl group is formed in the 17-position.

The process according to the invention can be carried out by reactingthe 16,17-oxido A -pregnene-3,20-dione,

or its 2l-hydroxy or 2l-acyloxy derivatives in the presence or absenceof a diluent, preferably at an elevated temperature, with the secondarybase corresponding to the desired end product.

Diluents are chosen among organic solvents which prove to be inertagainst the reaction components, such as lower alkanoles, dioxane etc.It is advantageous to use an excess of the secondary base according toFormula III. 'In case of reaction components or diluents having a lowboiling point the reaction can be carried out in a closed vessel. Owingto the fact that the 16,17-oxido-ring proves to be rather resistant tobases, the reaction is preferably carried out in presence of substanceshaving an accelerating effect upon the reaction. According to ourexperience water or phenol may be used advantageously as such substance,for in their presence the splitting of the epoxide ring and thesimultaneous addition of the base occurs already at lower temperaturesand within shorter time.

If the steroid compound used as starting material contains an acyloxygroup in the 2l-positi0n, this group may be split off entirely or partlyin the course of the reaction; thus hydroxyl group is for-med in the2l-position of the end product.

As secondary bases of the general formula III there can be used dialkylamines, such as dimethylamine, or dialkylamines substituted in the alkylgroups, such as diethanol amine, and heterocyclic secondary amines, suchas morpholine, methyl morpholine, piperidine, piperazine, pyrrolidineetc.

The following examples serve to illustrate the process according to theinvention.

Example 1 .3,16-Di-(N-M0rpholino)3,5-Pregnandiene- 1 7u-Ol-20-One Themixture of 3.3 g. 16a,l7u-oxidio-progesterone, 0.9 g. phenol and 10 ml.morpholine is stirred for 16 hours at a temperature of -135 C. Aftercooling the excess of morpholine is distilled off and the residue istr-iturated with methanol, sucked 01f, washed with methanol andrecrystallized from ethyl acetate. The product melts at 263-266 C.; [a]='121.7 (c.=1, chloroform).

Example 2.3,16-Dz'-(N-Piperidin0 -3,5-Pregna'ndiene- 17a-Ol-20-One Themixture of 3.3 g. 16a,17a-oxido-progesterone, 0.9 g. phenol and 10 ml.piperidine are heated in a sealed tube for 16 hours at a temperature ofC. The reaction product crystallizes while cooling. The excess ofpiperidine is distilled off, the residue is triturated with 30 ml.methanol, sucked oil and recrystallized from ethyl acetate. The productmelts at 212-216" C.; [a] ='-109 (c.='1, chloroform).

Example 3 .3,1 6-Di- (N -Pyrr0lidz'n0) -3,5 -Pregnandiene- J7a-Ol-20-OneThe mixture of 3.3 g. 16a,l7a-oxido-progesterone, 0.9 g. phenol and 10ml. pyrrolidine is heated in a sealed tube for 20 hours at a temperatureof C. The product crystallizes while cooling. It is triturated withmethanol, sucked off, washed with methanol and recrystallized frombenzene. The product melts at 267-272 C.; [a] -l2l (c.=l, chloroform).

Example 4.3,16-Di- (N-Dimethylamino) -3,5-Pregnandiene-17u-Ol-20-One Themixture of 6.6 g. 16a,17a-oxidoprogesterone, 1.8 g. phenol and 40 ml.dimethyl amine is kept for 20 hours in an autoclave at a temperature of-150 C. After cooling the product is triturated with methanol, suckedoff, washed with methanol and recrystallized from benzene. The productmelts at 240-246 C.; [a] =-143.5 (c.=l, chloroform).

What We claim is: 3. 3,16-di-(N-piperidino)-3,S-pregnandiene-17ao120- 1. A steroid derivative of the formula 20-one.

4. 3,16-di-(N-pyrrolidino)-3,5-pregnandiene-17a-o1-20- (3H3 one. (30 55. 3,16-di-(N-dimethy1arnino)-3,5 pregnandiene 17a- 01-20-0116.

WNRR 6. A process for the production of steroid derivatives substitutedby a hydroxyl group in the 17a-position and by basic groups in the 3-and 16-positions, which com- 10 prises reacting16a,17a-oxid0-progesterone with a secondary amine selected from thegroup consisting of di-(lower alkyU-amines, morpholine, piperidine andpyrrolidine.

wherein RR'N represents a member selected from the References Cited inthe file Of this patent group consisting of di-(lower alkyD-amino,morpholino, 15 piperidino and pyrrolidine. UNITED STATES PATENTS 2.3,16-di-(N-morpho1ino)-3,5-pregnandiene-17a-o1-20- 2,808,399 Dodson Oct.1, 1957 One

1. A STEROID DERIVATIVE OF THE FORMULA